The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure

Abstract

Rationale-Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.Objective-Previous work showed that adenosine A 2A antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice. The present work used a T-maze choice procedure to assess the effects of adenosine A 2A and A 1 antagonism.Materials and methods-With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical 44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food. Results-Haloperidol produced a dose-related (0.05-0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier arm. Co-administration of the adenosine A 2A receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related choice and latency. NIH Public AccessConclusions-Adenosine A 2A and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders.

Adenosine A_2A-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

“…In one study, motor effects of A 2A -receptor antagonism were accompanied by an inhibition of pimozide-induced increased expression of c-Fos in the VL neostriatum, the striatal area most closely associated with tremulous jaw movements [61]. Other studies indicated that A 2A -receptor antagonists inhibited haloperidol-induced oxidative damage [47] and reversed haloperidol-related impairment of decision-making in the T-maze choice procedure (a possible model of antipsychotic-induced anhedonia) [62]. Selective A 2A -receptor antagonists also have demonstrated efficacy in the treatment of Parkinson’s disease as adjunctive therapy [1,12,63], although nonselective A 2A -receptor antagonists (e.g.…”

A translational research framework for enhanced validity of mouse models of psychopathological states in depression

“…climbing, to retrieve it, and the other arm is consistently baited with a small amount of reward that is retrieved easily. Non-manipulated rats strongly prefer the large, demanding reward (Mott et al, 2009), thereby providing a basis for the study of any psychomotor fatigue induced by MDD-relevant genetic and environmental manipulations. As described above, relatively rapid reduction in grip strength has been demonstrated in MDD patients, and using an operant apparatus analogous to the human dynamometer test combined with positive reinforcement, grip strength can also be measured readily in rodents (Connolly et al, 2001).…”

Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation

“…Nevertheless, low doses of DA antagonists and accumbens DA depletions dramatically altered choice behavior when the high-density arm (four pellets) had the barrier in place, and the arm without the barrier contained an alternative food source (two pellets). Under these conditions, rats with impaired DA transmission showed decreased choice for the high-density arm that contained the barrier, and increased choice for the arm with less food that did not have a barrier [73][74][75]. More recently, a mouse version of the T-maze task has been developed [76].…”

“…The highdensity arm contained four food pellets, and the low-density arm contained two food pellets. Taken from [75].…”

“…Studies employing the T-maze barrier choice procedure demonstrated that the adenosine A 2A receptor antagonist, MSX-3, could reverse the effects of the D 2 antagonist haloperidol in both rats [75] and mice [76]. MSX-3 also reversed the effects of the D 2 antagonists haloperidol and eticlopride in rats responding on the concurrent lever pressing/chow feeding procedure [ .…”